Galbofloxacin: a xenometal-antibiotic with potent and efficacy against .

Siderophore-antibiotic drug conjugates are considered potent tools to deliver and potentiate the antibacterial activity of antibiotics, but only few have seen preclinical and clinical success. Here, we introduce the gallium(iii) complex of a ciprofloxacin-functionalized linear desferrichrome, Galbofloxacin, with a cleavable serine linker as a potent therapeutic for bacterial infections. We employed characterization using inhibitory assays, radiochemical, tracer-based uptake and pharmacokinetic assessment of our lead compound, culminating in efficacy studies in a soft tissue model of infection. Galbofloxacin exhibits a minimum inhibitory concentration of (MIC) 93 nM in wt , exceeding the potency of the parent antibiotic ciprofloxacin (0.9 μM). Galbofloxacin is a protease substrate that can release the antibiotic payload in the bacterial cytoplasm. Radiochemical experiments with bacterial strains reveal that Galbofloxacin is taken up efficiently using siderophore mediated, active uptake. Biodistribution of Galbofloxacin in a mouse model of intramuscular infection revealed renal clearance and enhanced uptake in infected muscle when compared to Ga-citrate, which showed no selectivity. A subsequent drug therapy study reveals efficient reduction in infection burden and sustained survival with Galbofloxacin for 7 days. Ciprofloxacin had no treatment efficacy at identical molecular dose (9.3 μmol kg) and resulted in death of all study animals in <24 hours. Taken together, the favorable bacterial growth inhibitory, pharmacokinetic and efficacy properties qualify Galbofloxacin as the first rationally designed Ga-coordination complex for the management of bacterial infections.